Robinow Syndrome, Autosomal Recessive 2

Mendelian MONDO:0032800 Pathograph 8 Show in embeddings browser Robinow Syndrome Skeletal Dysplasia

The NXN form: biallelic variants in nucleoredoxin, a thioredoxin-family redox protein that binds Dishevelled and regulates its availability for WNT signal transduction. It was found not by phenotype-led search but by screening the WNT5A interactome in Robinow families that were negative for the previously known genes — the same study that identified the FZD2 form. The interesting thing about this entity is that its inheritance and its phenotype point in different directions. It is recessive, like ROR2 disease, but quantitative phenotypic clustering places NXN probands with the DVL1, DVL2 and DVL3 probands — the dominant forms — rather than with ROR2 disease. So the severity gradient in Robinow syndrome tracks where in the pathway the lesion sits, not whether one or two alleles are hit. Nucleoredoxin acts at the Dishevelled step, and the phenotype follows the step rather than the dose.

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1
Inheritance
3
Pathophys.
3
Phenotypes
1
Gaps
8
Pathograph
1
Genes
2
Medical Actions
2
Differentials
2
References
🏷

Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE
ISDS Skeletal Nosology
mesomelic and rhizomesomelic dysplasias
👪

Inheritance

1
Autosomal recessive HP:0000007
Biallelic NXN variants co-segregating with the phenotype in two families. Sibling recurrence risk is 25%.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:29276006 SUPPORT Human Clinical
"In total, four families with variants in FZD2 were identified as well as three individuals from two families with biallelic variants in NXN that co-segregate with the phenotype."
States both the biallelic requirement and the co-segregation.
?

Discussions and Knowledge Gaps

1
Why does a recessive lesion at NXN produce a phenotype indistinguishable from the heterozygous DVL-related forms rather than from the recessive ROR2 form?
KNOWLEDGE GAP nxn_recessive_but_dominant_like_phenotype
Attached to
pathophysiology#Perturbed Dishevelled-Level WNT/PCP Signalling
The natural expectation is that two hit alleles give more severe disease than one, and ROR2 disease is indeed the severe end. NXN breaks that expectation: biallelic loss, but a phenotype clustering with heterozygous DVL1/DVL2/DVL3 probands. The most economical explanation is that severity tracks the position of the lesion in the cascade rather than allele dosage — receptor-level loss being worse than transducer-level perturbation — but that is an inference from a clustering analysis of a small cohort, not a measured mechanism. Functional comparison of NXN-null and ROR2-null signalling output in the same system would test it.
⚙

Pathophysiology

3
Biallelic NXN Loss of Function
Nucleoredoxin is a thioredoxin-family redox protein that binds Dishevelled and regulates its availability for WNT signal transduction. Losing it places the lesion one step upstream of Dishevelled itself — a regulator of the transducer rather than the transducer, the ligand, or the receptor.
NXN hgnc:18008 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NXN (hgnc:18008). hgnc:18008 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context NXN hgnc:18008 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns NXN (hgnc:18008). hgnc:18008 is a gene from the HUGO Gene Nomenclature Committee. zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
NXN redox regulation of Dishevelled GO:0016055 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves NXN redox regulation of Dishevelled, annotated with Wnt signaling pathway (GO:0016055), qualified as loss of function. GO:0016055 is a biological process from the Gene Ontology. ⇓ LOSS OF FUNCTION
Downstream
Perturbed Dishevelled-Level WNT/PCP Signalling Loss of the Dishevelled redox regulator perturbs transduction at the Dishevelled step.
Show evidence (1 reference)
PMID:29276006 SUPPORT Human Clinical
"Importantly, both FZD2 and NXN are relevant protein partners in the WNT5A interactome, supporting their role in skeletal development."
Places NXN as a WNT5A-interactome partner, the basis for treating its loss as an input to the same pathway.
Perturbed Dishevelled-Level WNT/PCP Signalling
The convergence point this entry shares with every other Robinow genotype. What is distinctive is where NXN enters: at the Dishevelled step, the same level as the DVL1 and DVL3 alleles — which is the most plausible explanation for the phenotypic clustering, since probands with biallelic NXN variants group with the DVL-related probands rather than with ROR2 disease despite sharing ROR2 disease's recessive inheritance.
non-canonical Wnt signaling pathway GO:0035567 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased non-canonical Wnt signaling pathway (GO:0035567). GO:0035567 is a biological process from the Gene Ontology. ↓ DECREASED Wnt signaling pathway, planar cell polarity pathway GO:0060071 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Wnt signaling pathway, planar cell polarity pathway (GO:0060071). GO:0060071 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Disrupted Planar Cell Polarity in Developing Skeleton and Face Perturbed transduction reaches the developmental programs PCP governs.
Show evidence (2 references)
PMID:35047859 SUPPORT Human Clinical
"Probands with biallelic NXN variants clustered together with the majority of probands carrying DVL1, DVL2, and DVL3 variants, demonstrating no phenotypic distinction between the NXN-autosomal recessive and dominant forms of RS."
The clustering result that this node's pathway-level argument rests on, and the reason the entry does not model this form on ROR2 disease.
PMID:35047859 SUPPORT Human Clinical
"Robinow syndrome (RS) is a genetically heterogeneous disorder with six genes that converge on the WNT/planar cell polarity (PCP) signaling pathway implicated (DVL1, DVL3, FZD2, NXN, ROR2, and WNT5A)."
Names NXN among the six convergent genes.
Disrupted Planar Cell Polarity in Developing Skeleton and Face
The shared endpoint: loss of the polarized, directional cell behaviour that PCP signalling governs, in the growth plate, the frontonasal midline and the genital tubercle. The developmental decomposition comes from the Ror2-null mouse and is inherited here by pathway membership rather than demonstrated for NXN — a weaker transfer than usual, since NXN sits at a different step of the pathway from ROR2 and the phenotypic clustering says the two are not equivalent.
chondrocyte differentiation GO:0002062 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased chondrocyte differentiation (GO:0002062). GO:0002062 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Mesomelic Limb Shortening Disordered growth plate chondrocyte behaviour shortens the middle limb segment.
Fetal Facies Midline outgrowth failure of the frontonasal region.
Genital Hypoplasia Reduced genital tubercle outgrowth.
Show evidence (1 reference)
PMID:29276006 SUPPORT Human Clinical
"These data support an initial hypothesis that Robinow syndrome results from perturbation of the Wnt/PCP pathway"
States the pathway-level model this node represents.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Robinow Syndrome, Autosomal Recessive 2 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

3
Eye 1
Fetal Facies VERY_FREQUENT Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35047859 SUPPORT Human Clinical
"RS is characterized by skeletal dysplasia and distinctive facial and physical characteristics."
Establishes the distinctive facial characteristics at the syndrome level; no NXN-specific facial series has been published, hence PARTIAL.
Other 2
Mesomelic Limb Shortening VERY_FREQUENT Mesomelia HP:0003027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mesomelia (HP:0003027). HP:0003027 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35047859 SUPPORT Human Clinical
"RS is characterized by skeletal dysplasia and distinctive facial and physical characteristics."
Establishes the skeletal dysplasia at the syndrome level. The NXN-specific severity profile comes from the clustering result rather than from a descriptive series, hence PARTIAL.
Genital Hypoplasia FREQUENT Hypoplastic male external genitalia HP:0000050 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplastic male external genitalia (HP:0000050). HP:0000050 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25577943 SUPPORT Human Clinical
"genital abnormalities (in males: micropenis / webbed penis, hypoplastic scrotum, cryptorchidism; in females: hypoplastic clitoris and labia majora)"
Describes the genital phenotype of the dominant forms, with which NXN probands cluster phenotypically. PARTIAL because it is not an NXN-specific observation.
🧬

Genetic Associations

1
NXN
Gene: NXN hgnc:18008 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NXN (hgnc:18008). hgnc:18008 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:29276006 SUPPORT Human Clinical
"In total, four families with variants in FZD2 were identified as well as three individuals from two families with biallelic variants in NXN that co-segregate with the phenotype."
Establishes NXN as a Robinow gene with co-segregating biallelic variants.
💊

Medical Actions

2
Genetic Counseling
Category: Counseling / Informational Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
A 25% sibling recurrence risk. Counselling here has a specific pitfall: the phenotype looks like the dominant forms, so a family assumed to have dominant disease on clinical grounds would be given the wrong recurrence risk until the molecular diagnosis is made.
Show evidence (1 reference)
PMID:35047859 SUPPORT Human Clinical
"Probands with biallelic NXN variants clustered together with the majority of probands carrying DVL1, DVL2, and DVL3 variants, demonstrating no phenotypic distinction between the NXN-autosomal recessive and dominant forms of RS."
Establishes that the clinical picture does not reveal the inheritance mode, which is what makes the counselling pitfall real.
Orthodontic and Supportive Care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Management follows the syndrome-level pattern: orthodontic treatment, corrective genital surgery where indicated, and surveillance. No NXN-specific management evidence exists.
Mechanism Target:
Disrupted Planar Cell Polarity in Developing Skeleton and Face — Manages the craniofacial and dental consequences of the PCP defect. Symptomatic; nothing here acts on the redox regulation of Dishevelled.
Show evidence (1 reference)
PMID:25577943 SUPPORT Human Clinical
"Orthodontic treatment is typically required."
Management guidance from the dominant-form chapter, applied here because the phenotypes cluster together. PARTIAL because it is not NXN-specific.
🔬

Diagnosis

1
Molecular Confirmation
Confirmed by biallelic NXN variants. In practice NXN is reached through a Robinow gene panel or exome rather than tested first, since the clinical picture does not distinguish it from the DVL-related forms — which is precisely what the phenotypic clustering showed.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:35047859 SUPPORT Human Clinical
"Pathogenic or likely pathogenic variants in genes associated with RS or RS phenocopies were identified in all 22 individuals"
Supports the high molecular yield of broad testing in a clinically ascertained Robinow cohort, which is how this form is reached.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Three individuals from two families in the report that established the gene, with occasional cases since. No denominator-based estimate exists.
Show evidence (1 reference)
PMID:29276006 SUPPORT Human Clinical
"In total, four families with variants in FZD2 were identified as well as three individuals from two families with biallelic variants in NXN that co-segregate with the phenotype."
Gives the cohort size on which the gene assignment rests.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Robinow Syndrome, Autosomal Recessive 2:

Autosomal Recessive Robinow Syndrome
Overlapping Features The ROR2 form — the other recessive Robinow entity, and the one this form is most likely to be assumed to resemble. It does not: ROR2 disease is more severe, with vertebral segmentation defects and rib fusions, while NXN probands cluster with the milder dominant forms.
Autosomal Dominant Robinow Syndrome 2
Overlapping Features The DVL1 form. Phenotypically the closest match despite the opposite inheritance mode, which is the central observation about this entity. Distinguished by inheritance pattern and by the DVL1-specific osteosclerosis.
{ }

Source YAML

click to show 
name: Robinow Syndrome, Autosomal Recessive 2
synonyms:
- RRS2
- NXN-related Robinow syndrome
- nucleoredoxin-related Robinow syndrome
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: robinow syndrome, autosomal recessive 2
  term:
    id: MONDO:0032800
    label: robinow syndrome, autosomal recessive 2
description: >-
  The NXN form: biallelic variants in nucleoredoxin, a thioredoxin-family redox
  protein that binds Dishevelled and regulates its availability for WNT signal
  transduction. It was found not by phenotype-led search but by screening the
  WNT5A interactome in Robinow families that were negative for the previously
  known genes — the same study that identified the FZD2 form.

  The interesting thing about this entity is that its inheritance and its
  phenotype point in different directions. It is recessive, like ROR2 disease,
  but quantitative phenotypic clustering places NXN probands with the DVL1,
  DVL2 and DVL3 probands — the dominant forms — rather than with ROR2 disease.
  So the severity gradient in Robinow syndrome tracks where in the pathway the
  lesion sits, not whether one or two alleles are hit. Nucleoredoxin acts at the
  Dishevelled step, and the phenotype follows the step rather than the dose.
parents:
- Robinow Syndrome
- Skeletal Dysplasia
notes: >-
  Scope. This entry covers the NXN form only (MONDO:0032800, RRS2). The ROR2
  recessive form is ``Autosomal_Recessive_Robinow_Syndrome``; the union is
  ``kb/groupings/Robinow_Syndrome.yaml``.

  Evidence base. Two families, three individuals. Nothing here rests on a large
  series, and the clinical phenotype is characterized mainly through the
  quantitative HPO clustering rather than through a descriptive case series. The
  entry is deliberately thinner than the ROR2 and DVL1 entries because the
  literature is thinner, not because it was curated less carefully; where a
  phenotype is asserted from the syndrome-level description rather than from NXN
  patients specifically, the evidence explanation says so.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A Mendelian developmental disorder of a defined signalling pathway.
  isds_skeletal_category:
  - classification_value: mesomelic_and_rhizomesomelic_dysplasias
    notes: >-
      ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (Unger et al.,
      PMID:36779427), group 15 "Mesomelic and rhizo-mesomelic dysplasias", row
      NOS 15-0100, listed as "Robinow syndrome, recessive type, NXN-related"
      (AR, no MIM number given in the table). The 2019 revision (Mortier et al.,
      PMID:31633310) numbered the same group 17.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Three individuals from two families in the report that established the gene,
    with occasional cases since. No denominator-based estimate exists.
  evidence:
  - reference: PMID:29276006
    reference_title: "WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In total, four families with variants in FZD2 were identified as well as
      three individuals from two families with biallelic variants in NXN that
      co-segregate with the phenotype.
    explanation: >-
      Gives the cohort size on which the gene assignment rests.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic NXN variants co-segregating with the phenotype in two families.
    Sibling recurrence risk is 25%.
  evidence:
  - reference: PMID:29276006
    reference_title: "WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In total, four families with variants in FZD2 were identified as well as
      three individuals from two families with biallelic variants in NXN that
      co-segregate with the phenotype.
    explanation: >-
      States both the biallelic requirement and the co-segregation.
pathophysiology:
- name: Biallelic NXN Loss of Function
  role: trigger
  biological_scale: MOLECULAR
  genes:
  - preferred_term: NXN
    term:
      id: hgnc:18008
      label: NXN
  genetic_context:
    gene:
      preferred_term: NXN
      term:
        id: hgnc:18008
        label: NXN
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  description: >-
    Nucleoredoxin is a thioredoxin-family redox protein that binds Dishevelled
    and regulates its availability for WNT signal transduction. Losing it places
    the lesion one step upstream of Dishevelled itself — a regulator of the
    transducer rather than the transducer, the ligand, or the receptor.
  biological_processes:
  - preferred_term: NXN redox regulation of Dishevelled
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0016055
      label: Wnt signaling pathway
  evidence:
  - reference: PMID:29276006
    reference_title: "WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Importantly, both FZD2 and NXN are relevant protein partners in the WNT5A
      interactome, supporting their role in skeletal development.
    explanation: >-
      Places NXN as a WNT5A-interactome partner, the basis for treating its loss
      as an input to the same pathway.
  downstream:
  - target: Perturbed Dishevelled-Level WNT/PCP Signalling
    causal_link_type: DIRECT
    description: >-
      Loss of the Dishevelled redox regulator perturbs transduction at the
      Dishevelled step.
- name: Perturbed Dishevelled-Level WNT/PCP Signalling
  role: central_effector
  biological_scale: CELLULAR
  description: >-
    The convergence point this entry shares with every other Robinow genotype.
    What is distinctive is where NXN enters: at the Dishevelled step, the same
    level as the DVL1 and DVL3 alleles — which is the most plausible explanation
    for the phenotypic clustering, since probands with biallelic NXN variants
    group with the DVL-related probands rather than with ROR2 disease despite
    sharing ROR2 disease's recessive inheritance.
  biological_processes:
  - preferred_term: non-canonical Wnt signaling pathway
    modifier: DECREASED
    term:
      id: GO:0035567
      label: non-canonical Wnt signaling pathway
  - preferred_term: Wnt signaling pathway, planar cell polarity pathway
    modifier: DECREASED
    term:
      id: GO:0060071
      label: Wnt signaling pathway, planar cell polarity pathway
  evidence:
  - reference: PMID:35047859
    reference_title: "Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Probands with biallelic NXN variants clustered together with the majority
      of probands carrying DVL1, DVL2, and DVL3 variants, demonstrating no
      phenotypic distinction between the NXN-autosomal recessive and dominant
      forms of RS.
    explanation: >-
      The clustering result that this node's pathway-level argument rests on,
      and the reason the entry does not model this form on ROR2 disease.
  - reference: PMID:35047859
    reference_title: "Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Robinow syndrome (RS) is a genetically heterogeneous disorder with six
      genes that converge on the WNT/planar cell polarity (PCP) signaling
      pathway implicated (DVL1, DVL3, FZD2, NXN, ROR2, and WNT5A).
    explanation: >-
      Names NXN among the six convergent genes.
  downstream:
  - target: Disrupted Planar Cell Polarity in Developing Skeleton and Face
    causal_link_type: DIRECT
    description: >-
      Perturbed transduction reaches the developmental programs PCP governs.
- name: Disrupted Planar Cell Polarity in Developing Skeleton and Face
  role: consequence
  biological_scale: TISSUE
  description: >-
    The shared endpoint: loss of the polarized, directional cell behaviour that
    PCP signalling governs, in the growth plate, the frontonasal midline and the
    genital tubercle. The developmental decomposition comes from the Ror2-null
    mouse and is inherited here by pathway membership rather than demonstrated
    for NXN — a weaker transfer than usual, since NXN sits at a different step
    of the pathway from ROR2 and the phenotypic clustering says the two are not
    equivalent.
  biological_processes:
  - preferred_term: chondrocyte differentiation
    modifier: DECREASED
    term:
      id: GO:0002062
      label: chondrocyte differentiation
  evidence:
  - reference: PMID:29276006
    reference_title: "WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These data support an initial hypothesis that Robinow syndrome results
      from perturbation of the Wnt/PCP pathway
    explanation: >-
      States the pathway-level model this node represents.
  downstream:
  - target: Mesomelic Limb Shortening
    causal_link_type: DIRECT
    description: >-
      Disordered growth plate chondrocyte behaviour shortens the middle limb
      segment.
  - target: Fetal Facies
    causal_link_type: DIRECT
    description: >-
      Midline outgrowth failure of the frontonasal region.
  - target: Genital Hypoplasia
    causal_link_type: DIRECT
    description: >-
      Reduced genital tubercle outgrowth.
phenotypes:
- category: Skeletal
  name: Mesomelic Limb Shortening
  description: >-
    Shortening of the middle limb segment. The severity profile matches the
    dominant DVL-related forms rather than the ROR2 recessive form.
  phenotype_term:
    preferred_term: Mesomelia
    term:
      id: HP:0003027
      label: Mesomelia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:35047859
    reference_title: "Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RS is characterized by skeletal dysplasia and distinctive facial and
      physical characteristics.
    explanation: >-
      Establishes the skeletal dysplasia at the syndrome level. The NXN-specific
      severity profile comes from the clustering result rather than from a
      descriptive series, hence PARTIAL.
- category: Craniofacial
  name: Fetal Facies
  description: >-
    The distinctive facial gestalt shared across Robinow genotypes.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:35047859
    reference_title: "Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RS is characterized by skeletal dysplasia and distinctive facial and
      physical characteristics.
    explanation: >-
      Establishes the distinctive facial characteristics at the syndrome level;
      no NXN-specific facial series has been published, hence PARTIAL.
- category: Genitourinary
  name: Genital Hypoplasia
  phenotype_term:
    preferred_term: Hypoplastic male external genitalia
    term:
      id: HP:0000050
      label: Hypoplastic male external genitalia
  frequency: FREQUENT
  evidence:
  - reference: PMID:25577943
    reference_title: "Autosomal Dominant Robinow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      genital abnormalities (in males: micropenis / webbed penis, hypoplastic
      scrotum, cryptorchidism; in females: hypoplastic clitoris and labia
      majora)
    explanation: >-
      Describes the genital phenotype of the dominant forms, with which NXN
      probands cluster phenotypically. PARTIAL because it is not an NXN-specific
      observation.
genetic:
- name: NXN
  gene_term:
    preferred_term: NXN
    term:
      id: hgnc:18008
      label: NXN
  relationship_type: CAUSATIVE
  notes: >-
    Nucleoredoxin, a thioredoxin-family binding partner of Dishevelled.
    Established on two families with co-segregating biallelic variants and
    corroborated by the gene's position in the WNT5A interactome. The evidence
    base is small; a third independent family would strengthen it considerably.
  evidence:
  - reference: PMID:29276006
    reference_title: "WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In total, four families with variants in FZD2 were identified as well as
      three individuals from two families with biallelic variants in NXN that
      co-segregate with the phenotype.
    explanation: >-
      Establishes NXN as a Robinow gene with co-segregating biallelic variants.
diagnosis:
- name: Molecular Confirmation
  description: >-
    Confirmed by biallelic NXN variants. In practice NXN is reached through a
    Robinow gene panel or exome rather than tested first, since the clinical
    picture does not distinguish it from the DVL-related forms — which is
    precisely what the phenotypic clustering showed.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:35047859
    reference_title: "Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic or likely pathogenic variants in genes associated with RS or RS
      phenocopies were identified in all 22 individuals
    explanation: >-
      Supports the high molecular yield of broad testing in a clinically
      ascertained Robinow cohort, which is how this form is reached.
differential_diagnoses:
- name: Autosomal Recessive Robinow Syndrome
  description: >-
    The ROR2 form — the other recessive Robinow entity, and the one this form is
    most likely to be assumed to resemble. It does not: ROR2 disease is more
    severe, with vertebral segmentation defects and rib fusions, while NXN
    probands cluster with the milder dominant forms.
- name: Autosomal Dominant Robinow Syndrome 2
  description: >-
    The DVL1 form. Phenotypically the closest match despite the opposite
    inheritance mode, which is the central observation about this entity.
    Distinguished by inheritance pattern and by the DVL1-specific osteosclerosis.
treatments:
- name: Genetic Counseling
  action_category: COUNSELING_INFORMATIONAL
  description: >-
    A 25% sibling recurrence risk. Counselling here has a specific pitfall: the
    phenotype looks like the dominant forms, so a family assumed to have
    dominant disease on clinical grounds would be given the wrong recurrence
    risk until the molecular diagnosis is made.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:35047859
    reference_title: "Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Probands with biallelic NXN variants clustered together with the majority
      of probands carrying DVL1, DVL2, and DVL3 variants, demonstrating no
      phenotypic distinction between the NXN-autosomal recessive and dominant
      forms of RS.
    explanation: >-
      Establishes that the clinical picture does not reveal the inheritance
      mode, which is what makes the counselling pitfall real.
- name: Orthodontic and Supportive Care
  description: >-
    Management follows the syndrome-level pattern: orthodontic treatment,
    corrective genital surgery where indicated, and surveillance. No NXN-specific
    management evidence exists.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Disrupted Planar Cell Polarity in Developing Skeleton and Face
    description: >-
      Manages the craniofacial and dental consequences of the PCP defect.
      Symptomatic; nothing here acts on the redox regulation of Dishevelled.
  evidence:
  - reference: PMID:25577943
    reference_title: "Autosomal Dominant Robinow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Orthodontic treatment is typically required.
    explanation: >-
      Management guidance from the dominant-form chapter, applied here because
      the phenotypes cluster together. PARTIAL because it is not NXN-specific.
discussions:
- discussion_id: nxn_recessive_but_dominant_like_phenotype
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why does a recessive lesion at NXN produce a phenotype indistinguishable
    from the heterozygous DVL-related forms rather than from the recessive ROR2
    form?
  attaches_to:
  - pathophysiology#Perturbed Dishevelled-Level WNT/PCP Signalling
  rationale: >-
    The natural expectation is that two hit alleles give more severe disease
    than one, and ROR2 disease is indeed the severe end. NXN breaks that
    expectation: biallelic loss, but a phenotype clustering with heterozygous
    DVL1/DVL2/DVL3 probands. The most economical explanation is that severity
    tracks the position of the lesion in the cascade rather than allele dosage —
    receptor-level loss being worse than transducer-level perturbation — but that
    is an inference from a clustering analysis of a small cohort, not a measured
    mechanism. Functional comparison of NXN-null and ROR2-null signalling output
    in the same system would test it.
references:
- reference: PMID:29276006
  title: "WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome."
- reference: PMID:35047859
  title: "Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability."
📚

References & Deep Research

References

2
PMID:29276006
WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome.
No top-level findings curated for this source.
PMID:35047859
Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability.
No top-level findings curated for this source.